Vehicle for topical delivery of anti-inflammatory compounds

ABSTRACT

A vehicle for topical application which contains a liquid eutectic mixture of hydrophobic compounds to improve solubility of pharmaceutically active component and enhance topical and transdermal delivery.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of U.S. patent applicationSer. No. 10/255,951, filed Sep. 27, 2002.

FIELD OF THE INVENTION

The present invention relates to the preparation of semisolidformulations for topical delivery of pharmaceutically activeingredients, designed for pain control and inflammation treatment.

BACKGROUND OF THE INVENTION

Topical pharmaceutical preparations of different types have been usedfor treatment of rheumatic and arthritic pain for decades. Semisolidcompositions comprise plant derivatives, such as capsaicin (red hotpepper stinging substance) or turpentine (pine tar component) ointments,homeopathic extract and liniments (Opodeldoc Rus), mustard plasters,menthol rubs, essential oil balms and many others were used for a longtime, mainly as local irritants. Such irritation improves local bloodflow, accelerates injured tissue recovery, and switches attention fromchronic pain from inflammation.

By including non-steroid anti-inflammatory drugs (NSAIDs) into ointmentor cream application onto the desired location allows for effectivecontrol of muscle and joint pain intensity. Moreover, when NSAIDs areapplied topically, local drug concentration in muscle and joint tissuesis significantly higher than in non-treated sites. Additionally, thereis no intensive metabolism in liver (so called “first-pass effect”)because such drugs do not pass through the liver before action.

The required amount of NSAIDs is lower than an oral dose to achievesimilar anti-inflammative and analgesic effects. The most common sideeffect of NSAIDs is serious irritation of stomach and gastro-intestinalmucosa. This is substantially diminished with local topicalapplications.

Topical NSAID formulations are very popular in Europe, Asia and Far Eastregions. Examples of such compositions include Voltaren Emulgel®(Voltarol™ in UK), a 1.16% Diclofenac diethylammonium emulsion creamwith isopropyl alcohol, Feldene® Gel (0.5% Piroxicam water-ethyl alcoholgel), Ibuprofen and Ketoprofen gels of different strengths (5-10%), and1-10% Indomethacin in alcohol. DMSO-containing creams and many otherformulations are widespread in many countries as OTC (over the counter)remedies for muscle pain, minor sport injuries, rheumatic and back paintreatment, etc.

Generally, topical NSAID preparations do not have attributableside-effects such as gastric irritation and internal bleeding.Advantageously, the compounds provide relatively fast action onset andmoderate efficacy in treatment of local muscle and joint pain. The mainproblems of these products is low drug loading due to low solubility inthe cream components. High loading can be reached by use of concentratedalcohols, i.e. ethyl alcohol, isopropyl alcohol with polyethylene glycoland propylene glycol suitable as solvents for NSAIDs. Drug loading ishigh and can easily reach 5-10% or greater, e.g., 5% Ibuprofen gel withisopropyl alcohol, 1% Indomethacin gel based on ethyl alcohol or even10% Indomethacin ointment with dimethylsulfoxide.

These solvents are widely used for gel preparation, but widespread useis often limited due to the proclivity for skin irritation. A furtherlimitation is realized in fast termination of action for gelpreparations since the drug precipitates from solution subsequent towater absorption from the body tissue. Further, solvents in highconcentration often irritate the skin due to drying and delipidisationand may initiate contact dermatitis and allergy. The drug which isinsoluble in water media and body fluids, precipitates in the upper skinlayers and does not penetrate, thus seriously limiting theanti-inflammatory action. Similar behavior has been observed forpolyethylene glycol (mixture of PEG-4000 and PEG-400) hydrophilictopical base compositions.

Traditional hydrophobic vehicles such as fixed oils, mineral oil,petrolatum, lanolin and wax based ointments, along with emulsion creams(either O/W or W/O type) are less irritating to human skin, but thesepresent another complication—solubility. Drug loading in such vehiclesis limited by the solubility of the drug in the lipid phase. Forexample, the solubility of Indomethacin in olive or corn oil is below0.2%, whereas Ketoprofen is about 1.5% and Piroxicam below 0.05%.According to Benita et at. “Submicron Emulsions as Colloidal DrugCarriers for Intravenous Administration: Comprehensive PhysicochemicalCharacterization”, J. Pharm Sci., 1993, Nov. 82 (11), pp. 1069-79, evenfor low drug loading, stability of the dispersed system is questionable.A 0.1% Indomethacin submicron emulsion lost stability after 1 monthstorage.

Use of more polar hydrophobic compounds may help to improve solubilityof NSAIDs. Tocopherol acetate, triethyl citrate, glycerin monolaurate,glycerin monooleate (Myverol™ 18-9) dissolve between 1.5 and 2 timesmore Indomethacin or Diclofenac (in acidic form). Nevertheless, thisloading is insufficient to obtain an effective NSAID emulsion.Transdermal adhesive systems such as skin patches and plasters withIndomethacin or Diclofenac present low efficacy by the same reasoning.

A further method to increase drug solubility in the oil phase is to usehighly polar compounds, miscible with the oil phase. Solvents such asEthoxyethylene glycol (Transcutol™), dimethylisosorbide (DMIS),Isopropylideneglycerin (Solketal™), ethoxylated furanyl alcohol(Glucofurol™) visibly boost drug implementing in the separatehydrophobic phase. However, upon mixing with water, most of the solventis extracted into the water and the dissolved drug precipitatesimmediately and almost entirely from the oil phase.

Recently developed submicron emulsions (SME) employed as a base forNSAIDs, provide very effective delivery and exert pronounced improvementfor drug action as discussed in Friedman et al. (U.S. Pat. No.6,113,921). However, low solubility of NSAIDs in a lipid phase of suchemulsions leads to shortened periods of efficacy and drug precipitationfrom the oil phase during storage. High loading, desirable for optimalactivity of topical NSAID preparation for SME is achievable only forhighly lipophilic compounds, such as Naproxen, Ketoprofen or Ibuprofenwith significantly lower anti-inflammatory activity.

Eutectic mixture use in topical applications is rather limited. Anexample is EMLA cream, developed by Astra-Zeneca. The liquid, formed bymixing two crystalline bases of local anesthetics, Lidocain andPrilocaln due to eutectic formation serves as an oil phase in the creamfor topical application. The cream, containing 5% of the oil phase,provides excellent stability and anesthetic action.

In view of the limitations in the anti-inflammatory drug art, thereexists a need for an improved composition which overcomes theshortcomings presently encountered.

SUMMARY OF THE INVENTION

It has been found that a eutectic mixture of camphor, menthol, thymoland similar compounds is a powerful solvent for non-steroidalanti-inflammatory drugs and other substances. The solubility ofIndomethacin, Diclofenac, or Ketoprofen in the mixture increased between3 and 20 fold. As a particular advantage, the eutectic mixture was foundto be safe, non-toxic and present synergistic behavior in theanti-inflammatory action of NSAIDs due to the anti-inflammatoryproperties of camphor and skin penetration enhancing properties ofmenthol.

The eutectic mixture can be combined with pharmaceutically acceptableoils and lipids and included, into topical formulations. Thecompositions were found to allow much higher drug loading than existingointment bases and creams, showed no skin irritation and providedenhanced delivery properties for incorporated drugs.

Prior to embracing on a discussion of the preparation, some generalproperties of menthol and camphor will be established.

The menthol used was (1R, 2S, 5R)-5-methyl-2-(1-methyethyl)-cyclohexanolwith a molecular weight of 156.27 and melting point of 42° C. Mentholgenerally has a peppermint odor. It is well known as a skin irritant andpenetration enhancer, as discussed in Tsuk (U.S. Pat. No. 4,933,184). Itis widely used in many topical formulations for relief of arthritic andrheumatic pain. Natural L-menthol exerts a cooling or refreshingsensation due to direct interaction with cold sensitive receptors in theskin. This was established in the Handbook of Pharmaceutical Excipients,Third Edition, ed. A. H. Kibbe, Pharmaceutical Press, London, U.K.,2000, pp. 334-335. Menthol has been used as mild local anesthetic and asvolatile aromatic component for breath relief in obstruction and coldtreatment in Hughes et al., (U.S. Pat. No. 5,322,689).

Similar properties are known for camphor1,7,7-trimethylbicyclo[2,2,1]heptanone-2, having a molecular weight of152.24. Camphor has a high melting point (180° C.) and is a veryvolatile substance with strong pine-like odor that sublimes even at roomtemperature and pressure. Initially, camphor found use as a stimulant,but now camphor is mainly used as a component in topical preparations.It is often used in nasal decongestants and aromatic compositions.

Either menthol or camphor separately or in combination are widely usedin topical formulations, mainly due to their irritant action, receptorinteraction and specific traditional odor, frequently associated withtime-honored remedies. Ben Gay™ ointment, Tiger™ balm, Menthol Chest Ruband similar compositions are well known and popular.

Certain external analgesic products containing between 10% to 60% methylsalicylate, more than 3% to 11% camphor and 1.25% to 16% menthol, eithersingly or in combination, cause irritation or mild inflammation of theskin for the purpose of relieving pain in muscles, joints, or visceradistal to the site of application by stimulating depressing cutaneoussensory receptors, discussed in Ivy et al. (U.S. Pat. No. 5,013,726).

Topical preparations for joint relief include that provided for in Langet al. (U.S. Pat. No. 4,731,200) for an aqueous-alcohol compositioncontaining benzylidene-camphor derivatives, Ivy et al. (U.S. Pat. No.5,013,726) for a lotion containing methyl salicylate, camphor andmenthol, Ivy et al. (U.S. Pat. No. 5,124,320) for an analgesic lotioncontaining menthol and camphor, Heywang et al. (U.S. Pat. No. 5,144,081)for a pharmaceutical composition containing camphor and Singh (U.S. Pat.No. 5,175,152) for a composition with methyl salicylate, menthol andcamphor.

These substances have been advertised for use in relieving joint pain,such as the elbow, knee, thumb area, ankle, neck, wrist, hand andfinger, shoulder, etc.

To improve solubility of non-steroidal anti-inflammatory drugs, acomplex mixture of surfactants, polyglycol(s) and glycerides has beenused in combination with polymers and sodium or potassium hydroxidesolutions as established in Morton et al. (U.S. Pat. No. 5,376,688).

In Kaplun-Fischoff et al., “Testosterone Skin Permeation Enhancement byMenthol Through Formation of Eutectic with Drug and Interaction withSkin Lipids”, J. Pharm Sci. 1997,. December, 86 (12) pp. 1394-9, theresearchers observed that menthol forms a eutectic mixture withcrystalline testosterone. The formed mixture is not liquid, but thecomposition demonstrated a significant improvement in transdermalpenetration of testosterone. According Kaplun-Frischoff et al., mentholaffects skin permeation by a dual mechanism: by forming a eutectic withthe penetrating compound, thereby increasing its solubility in skinceramides and by altering the barrier properties of the stratum corneum.

A careful investigation of existing compositions containing menthol andcamphor in different ratios showed that there is no one example of thespecific use of menthol and camphor in combination as eutectic mixturein order to improve solubility of an included drug. Allanti-inflammatory components used in such formulations are liquid(methylsalycilate, benzylnicotinate, etc.) and easily miscible with oilcomponents of the creams or ointments. There is no limitation forsolubility, and these topicals can contain up to 60% of activecomponent, e.g., methylsalycilate), Altadonna (U.S. Pat. No. 5,853,768).

In the documentation there has not been a recognition of amenthol-to-camphor ratio in the eutectic region. In all cases, theexisting preparations are used only due to their mild irritative oranti-inflammatory activity (camphor, nicotinic acid derivatives) or skinpenetration enhancement properties of menthol itself.

It has now been recognized that a radical increase of drug solubility ina eutectic mixture of polar hydrophobic compounds allows preparation ofeffective and safe topical formulations with these drugs for externalapplication.

One object of one embodiment of the present invention is thus to providea vehicle for topical delivery of a pharmaceutically active component,comprising a liquid eutectic mixture containing a hydrophobic component.

A further object of one embodiment of the present invention is toprovide a composition for topical delivery comprising an oil-in-water orwater-in-oil emulsion or microemulsion, wherein the oil phase of theemulsion comprises a vehicle as set forth in claim 3.

A still further object of one embodiment of the present invention is toprovide a method for increasing the solubility of a pharmaceuticallyactive component in a vehicle for topical delivery of thepharmaceutically active component comprising providing apharmaceutically active component; providing at least two compoundsselected from the group consisting of camphor, menthol, thymol,resorcinol, phenol or substituted phenol derivatives; and forming aeutectic mixture containing the pharmaceutically active component and atleast two members whereby the mixture contains a greater amount ofsolubilzed active component relative to a non eutectic mixture.

Having thus described the invention, reference will now be made to theaccompanying drawings illustrating preferred embodiments.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graphical representation of Diclofenac (free acid)solubility in a mixture of MCT and a menthol/camphor mixture;

FIG. 2 is a graphical representation of Indomethacin solubility inoleaginous vehicles and in a menthol/camphor vehicle;

FIG. 3 is a graphical representation of Piroxicam solubility inoleaginous vehicles and in a eutectic vehicle;

FIG. 4 is a graphical representation of drug content change duringstorage; and

FIG. 5 is a graphical representation of comparative anti-inflammatoryactivity of topical formulations.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

A mixture of equimolar amounts of crystalline camphor and menthol atroom temperature immediately led to liquefied crystals. This mixture wasused in the preparations as an effective solvent for some NSAIDcompounds.

FIG. 1 graphically represents the solubility of Diclofenac (as freeacid) in mixtures of medium chain triglycerides (MCT, standard oilvehicle, Labrafac® TGCC) with different levels of added menthol-camphoreutectic mixture. Diclofenac saturation concentration at 25° C. wasevaluated by HPLC. Solubility in a pure equimolar menthol-camphoreutectic mixture was found to be 11.8 times higher than in pure MCT.

Similar behavior was observed also for Indomethacin, illustratedgraphically in FIG. 2. The maximum solubility in an equimolar eutecticmenthol-camphor mixture is 160 mg/ml, compared with 2 mg/ml in the soyoil or 4.8 mg/ml in MCT oil. For comparison, Ho et. al. “PenetrationEnhancement by Menthol Combined with a Solubilization Effect in a MixedSolvent System”, J. Controlled Release 1998, February 12; 51 (2-3), pp.301-11, investigated the influence of menthol addition (up to 12% byweight) as solubility enhancer for Indomethacin in differentpharmaceutical vehicles such as water, ethanol, propylene glycol andtheir combinations. In any case the maximum solubility hardly reached 2%(approximately 20 mg/ml).

In FIG. 3, further graphic data are presented for Piroxicam.

Piroxicam solubility is significantly lower than aromatic NSAIDs,however, use of the eutectic menthol-camphor mixture increased drugsolubility at room temperature between 8 and 11 times, from 0.35 mg/mlin MCT to 2.9-3.2 mg/ml in pure eutectic mixture and to 1.8 mg/ml in MCTwith 60% menthol-camphor (1:1) content.

If alpha-tocopherol or tocopherol acetate is used as the oil phase,solubility can reach 30-35 mg/ml for a tocopherol-menthol-camphorcomposition 5:3:3 (parts by weight).

Use of other ratios for menthol-camphor eutectic mixture (e.g., 2:1 or1:2; 3:4 or 4:3) also improves solubility for most of the investigatedsubstances, but to a slightly lower extent. Very significant improvementin solubility was achieved with replacement of menthol for anothereutectic forming substance, thymol (2-isopropyl-5-methylphenol, thymeoil component).

Obtained solutions of NSAIDs in lipid phase containing menthol-camphoror another eutectic mixture vehicle are stable in wide temperature rangeand non-irritating for human and animal skin (Dreize' test). Based onthese observations different topical formulations with NSAIDs wereprepared and will now be discussed in the examples.

EXAMPLE 1 Indomethacin 1% Cream

TABLE 1 CREAM INGREDIENTS % Per 250 g Indomethacin USP 1.00 2.5 MediumChain Triglycerides (Labrafac ® 4.00 10 CCTG) Soy Lecithin(Phospholipon ® S-80) 1.00 2.5 (±) Camphor USP 3.00 7.5 L-(−)-MentholUSP 3.00 7.5 Tween ™-80 (Polysorbate 80, USP) 1.60 4.0 TPGS (Tocopherolpolyethylene glycol 0.80 2.0 1000 succinate) Sodium Ethylenediaminetetraacetate 0.10 0.25 (EDTA sodium) Carbopol ® 971 P 1.50 3.75 GlycerinUSP 2.50 6.25 Water 81.50 203.75Vehicle (Eutectic Mixture) Preparation:

(±) Camphor and L-Menthol were mixed together during heating at between40 and 50° C. until a clear liquid was obtained.

Oil Phase Preparation:

Soy lecithin, MCT oil and TPGS were mixed together at 45° C. until ahomogenous solution was obtained. Tween™-80 as then added, followed bythe addition of the eutectic mixture vehicle. The mixture was stirreduntil completely dissolved. Indomethacin (USP grade) was added to thewarm mixture and stirred for 10 minutes at 45° C. until completelydissolved.

Water Phase Preparation:

EDTA disodium salt, glycerin and Tween™-80 were added to water (90% ofcalculated amount) and stirred until completely dissolved.

Emulsification:

The solution was combined with the oil phase, mixed thoroughly usingappropriate mixer and homogenized using high pressure homogenizer(Avestin® C-5) at 8,000-12,0009 psi, (600-800 bar). The mixture waspassed through the homogenizer between 2 and 3 times.

Cream Preparation:

In a separate vessel Carbopol® 971 P was mixed with 10% of calculatedamount of water and soaked for between 2 and 6 hours. Carbopol® pastewas combined with the homogenized emulsion using a high shearrotor-stator type mixer (Omni GLH mixer) at 18,000-24,000 rpm.Triethanolamine was added gradually while mixing until the desired pHand viscosity were achieved.

EXAMPLE 2 Indomethacin 2% Cream

The composition was prepared in accordance with the methodology ofExample 1. TABLE 2 CREAM INGREDIENTS Per 100 g Per 1000 Lipid PhaseIndomethacin USP 2.00 20.00 Medium Chain Triglycerides 8.00 80.00 EggLecithin S-75 2.00 20.00 (±) Camphor USP 6.00 60.00 L-(−)-Menthol USP6.00 60.00 Tween ™-80 (Polysorbate-80 USP) 2.00 20.00 TPGS (Tocopherolpolyethylene glycol 0.80 8.00 1000 succinate) Water Phase SodiumEthylenediaminetetraacetate 0.10 1.00 Bronopol ® (2-Brom-2-nitro-1,3-0.10 1.00 Triethanolamine 0.50 5.00 Ultrez ™ 10 0.50 5.00 Glycerin 2.2022.00 Water 69.80 698.00

Bronopol® (2-Brom-2-nitro-1,3-propanediol) was added to the water phaseas an antibacterial preservative. Ultrez™was used as a viscosityregulating component instead of Carbopol® without the preliminaryhydration step as set forth in Example 1.

EXAMPLE 3 Diclofenac Sodium 1% Cream

The composition of the emulsion for 1% Diclofenac cream presented inTable 3. The cream contains approximately 14% of the oil phase with aratio MCT:Camphor:Menthol of 6:3:4. TABLE 3 Emulsion part of Diclofenacsodium 1% cream. Per 100 g CREAM INGREDIENTS cream Medium ChainTriglycerides (Labrafac ® CCTG) 6.00 (±) Camphor USP 3.00 L-(−)-MentholUSP 4.00 Tocopherol succinate 0.02 Soy Lecithin (Phospholipon ® S-80)0.12 Tween-80 (Polysorbate - 80) 2.00 DICLOFENAC Sodium USP 1.00 Water80.38 Hydrochloric acid 1N 3.5

The oil phase was prepared by dissolving MCT, oil Tocopherol succinate,lecithin, camphor, and menthol at 45° C.

The water phase was prepared by dissolving Diclofenac sodium andTween™-80 in hot 85° C. purified water.

After mixing the warm oil and hot water phases, hydrochloric acid wasadded to coarse emulsion while intensive stirring. The pH was adjustedto between 3.5 and 4.2. Homogenization was conducted as described inExample 2. After a fine emulsion was obtained, it was filtered through0.45 micron PTFE membrane filter. The emulsion was used for creampreparation by addition of Carbopol® 971 as a gelling agent to a finalconcentration of 1.5% with pH adjustment to between 4.5 and 5.0.

1.5% Diclofenac sodium emulsion (Example 3A, high loading) was preparedby a similar manner. The composition is identical to that tabulated inTable 3. Balance was adjusted with water and hydrochloric acid.

EXAMPLE 4 Ibuprofen 5% Cream

5% Ibuprofen cream was prepared as described in The composition of theemulsion for 5% Diclofenac cream is presented in Table 4. The creamcontains approximately 26% of the oil phase with a ratioMCT:Camphor:Menthol of approximately 4.25:1:1. TABLE 4 CREAM INGREDIENTSPer 100 g Per 300 Ibuprofen 5.00 15.00 Medium Chain Triglycerides 13.7541.25 Soy Lecithin (Phospholipon ® S-80) 1.20 3.60 (±) Camphor USP 3.259.75 L-(−)-Menthol USP 3.25 9.75 Tween ™-80 (Polysorbate-80, USP) 2.006.00 TPGS (Tocopherol polyethylene glycol 0.80 2.40 1000 succinate)Sodium Ethylenediamine tetraacetate 0.10 0.30 (EDTA sodium) Bronopol ™0.10 0.30 Triethanolamine 1.00 3.00 Carbopol ® 934P 1.00 3.00 Glycerin2.20 6.60 Water 66.35 398.10

EXAMPLE 5 Piroxicam 0.5% Cream

The composition was prepared by the method described in Example 4, butL-(−)-menthol was replaced with thymol (2-isopropyl-5-methylphenol). Thecream contained approximately 28% of the oil phase with a ratioMCT:Camphor:Thymol:Tocopherol acetate of approximately 2:5:5:2. TABLE 5CREAM INGREDIENTS Per 100 g Per 250 Piroxicam 2.00 5.00 Medium ChainTriglycerides 3.00 7.50 Soy Lecithin (Phospholipon ® S-80) 2.00 5.00 (±)Camphor USP 7.50 18.75 Thymol 7.50 18.75 Tween ™-80 (Polysorbate-80,USP) 2.50 6.25 Tocopherol acetate (Vitamine E 2.00 5.00 acetate) EDTA0.10 0.25 Carbopol ® 934P 1.50 3.75 Glycerin 2.20 5.50 Triethanolamine0.90 2.25 Water 69.70 174.25

EXAMPLE 6 Reference

Emulsion with Indomethacin, prepared according to U.S. Pat. No.6,113,921. TABLE 6 Per 100 g cream 0.5% Indo 1.0% Indo (low (high CREAMINGREDIENTS (loading) loading) Indomethacin 0.5 1.0 Medium ChainTriglycerides (MCT oil) 17.0 17.0 Egg Lecithin (Phospholipon ® E-80) 0.80.8 Emulphor EL-620 (polyethoxylated 1.6 1.6 castor oil) Carbopol ® 9401.7 1.7 Glycerin 2.2 2.2 EDTA sodium salt 0.05 0.05 Tocopherol acidsuccinate 0.04 0.05 Triethanolamine 0.65 0.65 Water 75.3 74.5

Indomethacin (0.5 g for low loading and 1.0 g for high loadingemulsions) was dissolved in a preheated (60° C.) mixture of egglecithin, tocopherol succinate and MCT oil. This mixture was emulsifiedwith a water phase (water with Emulfor EL-620, EDTA sodium and glycerin)using a high shear mixer for 5 minutes at 20,000 rpm to form anemulsion.

Further treatment of the emulsion was conducted in a high pressurehomogenizer at 800 bar (12,000 psi) for 6 cycles. Thereafter, theemulsion was cooled to room temperature, and pH was adjusted to between5.6 and 6.5. Part of emulsion was gelled using Carbopol® 940 to form acream; another part was stored at room temperature in tightly closedamber glass containers for 6 months to observe the physical stability.

EXAMPLE 7 Diclofenac Sodium 1.0% and 1.5% Creams

Diclofenac sodium (1.0% and 1.5% drug loading) emulsions were preparedas described in Example 3 and 3A.

To estimate drug precipitation, the stored emulsion samples either forthe reference Example 6, low and high loaded or invention related(Examples 1 and 2) were filtered through PTFE membrane filters. TheIndomethacin content in the filtrates was measured using the HPLCmethod. FIG. 4 illustrates the results.

A low loaded emulsion, prepared in accordance with U.S. Pat. No.6,113,921, showed reasonable stability during storage, but with anincrease in the initial Indomethacin loading, the final concentration ofnon-precipitated drug decreased drastically. In contrast, the eutecticmixture vehicle emulsion, prepared in accordance with the presentinvention, maintained drug content.

Similar results have been obtained for Diclofenac sodium emulsions. In acomposition containing 1% of the drug, stability for both formulationswas observed. In a composition containing 1.5% Diclofenac sodiumemulsion in the menthol-camphor eutectic mixture, stability was observedfor at least 3 months at room temperature, while the identically loadedreference emulsion demonstrated significant drug precipitation duringthe same period.

EXAMPLE 8 Salicylic Acid Trolamine Cream

TABLE 7 Component % Oil Phase Tocopherol acetate (synth.) 3.0 Myvacet ™9-45K (Quest) 9.0 L-Menthol (USP) 2.0 DL-Camphor (USP) 2.0 Cremophor ®EL (BASF) 4.0 Supersat ® AWS (RITA) 2.0 Lecithin (Phosal 53 MCT) 1.5Ethyl alcohol 1.5 Estol ® 1540 (Ethylhexyl Cocoate, 3.0 Uniguema)Crotix ® (Croda) 2.0 Surfhope ® C-1601 (Mitsubishi) 2.0 Surfhope ®C-1816 (75-25) 2.0 (Mitsubishi) Salicylic acid 7.30 Water phaseTriethanolamine USP/NF 7.70 Bronopol ™ (BASF) 0.10 Water purified 50.90Total 100.00

Cream containing salicylic acid was prepared using a different set ofsurfactants. Salicylic acid was dissolved in the oil phase of thecomposition, with triethanolamine added to the water phase. Afteremulsification viscosity was adjusted using Crotix® (Croda) sinceCarbopol® was found inappropriate as a thickener. Anti inflammatoryactivity “in vivo”:

Investigations on animals (rats, carrageenan induced paw edema model)showed significant anti-inflammatory action of the topically appliedcompositions containing the eutectic vehicle. The results areillustrated in FIG. 5. From a review of FIG. 5, it is evident that theanti-inflammatory efficacy of the formulations of the present invention(ARX) is superior. This is a consequential result of the increasedsolubility and thus amount of the active ingredient. TABLE 8 Area Underthe Curve (AUC) ratio for edema volume (calculated by trapezoidal rulefor t = 0-6 hours). GROUP Ratio, % (±RSD) Control (nontreated) 100%(±28%) Indomethacin cream (ex. 2)  32% (±12%) 2 mg of Indomethacin/ratIndomethacin gel (Methacin ™, Sumitomo Pharm.) 114% (±39%) 2 mg ofIndomethacin/rat Diclofenac sodium cream (ex. 3)  30% (±14%) 2 mg ofDiclofenac sodium/rat Voltaren ® Emulgel ®  82% (±9%) 2 mg ofDiclofenac/rat Salicylic acid trolamin cream (ex. 8)  65% (±18%) (15 mgof salicylate/rat) Marketed Trolamine Salicylate cream (Aspercream)  89%(±42%) (15 mg of salicylate/rat)

The area under the curve reflects the duration and intensity ofcarrageenan induced inflammation(units are hr*mcl); the graeter theedema volume, the higher the inflammation and vice versa. A decrease ofAUC corresponds to a decrease of inflammation. AUC for the contol(non-treated) group was assigned to 100%. According to table 8Indomethacin in the eutectic-based formulation is almost 3 times moreactive than the same dose of Indomethacin in a conventional cream.Salycilate trolamine in the proposed vehicle demonstrates 50% higheranti-inflammatory activity.

Although embodiments of the invention have been described above, it isnot limited thereto and it will be apparent to those skilled in the artthat numerous modifications form part of the present invention insofaras they do not depart from the spirit, nature and scope of the claimedand described invention.

1. A vehicle for topical delivery of a pharmaceutically activecomponent, comprising a liquid eutectic mixture containing a hydrophobiccomponent.
 2. The vehicle as set forth in claim 1, wherein saidhydrophobic component is selected from the group consisting ofpharmaceutically acceptable glycerin esters, aliphatic esters, aromaticesters, waxes, lipids, fats, lipid soluble vitamins, hydrocarbons,silicone polymers, tocopherols, tocotrienols and related compounds, ormixture thereof.
 3. The vehicle as set forth in claim 1, wherein theratio of said hydrophobic component and liquid eutectic mixture are in aratio of between 1:10 to 10:1.
 4. The vehicle as set forth in claim 1,wherein the ratio of said hydrophobic component and liquid eutecticmixture are in a ratio of between 1:3 to 3:1.
 5. The vehicle as setforth claim 1, wherein said eutectic mixture comprises at least twocompounds selected from the group consisting of camphor, menthol,thymol, resorcinol, phenol or substituted phenol derivativesThe vehicleas set forth claim 5, wherein said eutectic mixture is liquid at ambienttemperature.
 6. A composition for topical delivery comprising anoil-in-water or water-in-oil emulsion or microemulsion, wherein the oilphase of said emulsion comprises a vehicle as set forth in claim
 3. 7.The composition as set forth in claim 6, wherein said pharmaceuticallyactive component is dissolved in said oil phase of said emulsion ormicroemulsion.
 8. The composition as set forth in claim 7, wherein saidoil phase comprises between 5% and 80% of said composition.
 9. Thecomposition as set forth in claim 7, further including a surfactant. 10.The composition as set forth in claim 9, wherein said pharmaceuticallyactive component is selected from anti-inflammatory drugs.
 11. Thecomposition as set forth in claim 10, wherein said anti-inflammatorydrugs are selected from group of non-steroidal anti-inflammatory drugs(NSAIDs).
 12. The composition as set forth in claim 11, wherein saidanti-inflammatory drugs are selected from the group consisting ofindomethacin, diclofenac, ketorolac, piroxicam, meloxicam, tenoxicam,ketoprofen, flurbiprofen, ibuprofen, nimesulide, naproxen, rofecoxib,celecoxib and salicylic acid.
 13. The composition as set forth in claim10, further including additional pharmaceutically active components,pharmaceutically acceptable surfactants, viscosity regulating agents,antibacterial preservatives, skin penetration enhancers, fragrances andcolorants.
 14. The composition as set forth in claim 9, wherein saidsurfactant is non-ionic surfactant, phospholipid or mixture thereof. 15.A method for increasing the solubility of a pharmaceutically activecomponent in a vehicle for topical delivery of said pharmaceuticallyactive component, comprising: providing a pharmaceutically activecomponent; providing at least two compounds selected from the groupconsisting of camphor, menthol, thymol, resorcinol, phenol orsubstituted phenol derivatives; and forming a eutectic mixturecontaining said pharmaceutically active component and said at least twomembers whereby said mixture contains a greater amount of solubilzedactive component relative to a non eutectic mixture.
 16. The method asset forth in claim 15, wherein said two selected compounds are camphorand menthol.
 17. The method as set forth in claim 15, wherein saidpharmaceutically active component comprises a non steroidalanti-inflammatory drug (NSAID).
 18. A composition for topical deliveryhaving an increased amount of a solubilized pharmaceutically activecomponent comprising an emulsion selected from the group consisting ofan oil-in-water, water-in-oil and microemulsion, wherein said oil phaseof said emulsion comprises a vehicle as set forth in claim 3, whereinsaid hydrophobic component is selected from the group consisting ofpharmaceutically acceptable glycerin esters, aliphatic esters, aromaticesters, waxes, lipids, fats, lipid soluble vitamins, hydrocarbons,silicone polymers, tocopherols, tocotrienols and related compounds, ormixture thereof, said eutectic; mixture comprising at, least two membersselected from the group consisting of camphor, menthol, thymol,resorcinol, phenol or substituted phenol derivatives; and apharmaceutically active component, said composition having an increasedsolubilized amount of said pharmaceutically active component relative toa non eutectic composition.